The growth in the use of living kidney donors makes it imperative to study possible adverse, long-term consequences of donation. This prospective cohort study will address whether donation increases the risk of developing end-stage kidney disease (ESRD) and/or increases the risk of cardiovascular disease (CVD). Pairs of living unrelated or distantly related kidney transplant donors and normal sibling controls will be enrolled. It has been argued that the there is a gradual, long-term, compensatory GFR increase that offsets the normal age-associated decline in GFR, and thereby reduces the risk for ESRD. This proposal will make serial determinations of GFR during the first 3 years after donation to determine when the maximum post-donation GFR occurs. This will set the stage for long-term follow-up studies to determine how much the subsequent age-related declines in GFR increase the risk of ESRD. In addition, a number of observational studies report that patients with mild reductions in GFR are at increased risk for CVD. While CVD risk factors may cause kidney damage, a growing amount of circumstantial evidence suggests that a mild reduction in GFR could adversely affect blood pressure, plasma lipids, glucose homeostasis, homocysteine, and even systemic inflammation. These effects may be most pronounced in the growing number of individuals who develop obesity and the metabolic syndrome. Living kidney donation makes it possible to study the effects of moderate reductions in GFR on CVD risk factors prospectively, using comparable siblings as normal controls. Using unrelated and distantly related donors will allow us to study the effects of donation per se, independent of genetic predisposition from having a close relative with kidney disease. Altogether, this study will provide useful information that will improve the informed consent for living kidney donors and enhance our knowledge of the role of the kidney, if any, in CVD.